The present invention relates to antagonists having affinity for xcex11B adrenoceptor.
Noradrenaline and adrenaline play important roles as neurotransmitters of the sympathetic nerve system or as vasoactive hormones in the regulation of physiological functions.
These noradrenaline and adrenaline transmit information into the cell by binding with receptors on a cell menbrane. The receptors were initially classified as a receptors and xcex2 receptors by Ahlquist (Am. J. Physiol., 153, 586(1948)), and thereafter, the xcex1 receptors were classified as xcex11 receptors and xcex12 receptors, and the xcex2 receptors were classified as xcex21 receptor and xcex22 receptor.
Of these adrenoceptors, it has been cleared that xcex11 receptors are important receptors which are associated with a variety of physiological activities such as vascular smooth muscle contraction, pupil dilator muscle contraction, cardiac muscle contraction, urethral smooth muscle contraction, renin secretion in the kidney, glycogenolysis in the liver, and lipolysis in fat cells.
The xcex11 receptors have further been classified as three subtypes, xcex11a, xcex11b, and xcex11d, by means of molecular biological techniques advanced in recent years (Pharmacol. Rev., 47, 267(1995)). Initially, there was some confusion between the molecular-biological classification using clones and the pharmacological classification, but the classification is now unified such that xcex11a, xcex11b, and xcex11d receptors, which are classified based on clone receptors, respectively correspond to xcex11A, xcex11B, and xcex11D receptors, which are pharmacologically classified.
Each of the xcex11 receptor subtypes is considered to exhibit pharmacological and tissue specificities, and it is very important to provide compounds having selectivity for each of the xcex11 receptor subtypes in order to elucidate physiological activities mediated by individual receptor subtypes and to remedy diseases in which they are involved.
Prazosin is widely used as a therapeutic agent for hypertension at present and has been already known to have no selectivity for the xcex11 receptor subtypes. Then, a multiplicity of compounds have been synthetically obtained, and 5-methylurapidil and KMD-3213, for example, have been developed as compounds having high selectivity for xcex11A receptor (Exp. Opin. Invest. Drugs, 6, 367(1997); Mol. Pharmacol., 48, 250(1995)). Experiments using these compounds having high selectivity for the xcex11A receptor suggested that the xcex11A receptor is deeply concerned in urethral smooth muscle contraction, and it is now under study to apply xcex11A receptor antagonists as therapeutic agents for dysuria due to prostatic hypertrophy (New Current, 7, 14(1996)).
In contrast, there are very few reports on compounds e - having selectivity for the xcex11B receptor, and spiperone and AH 1110A presently reported are not sufficient in their selectivity and affinity (Trend. Pharmacol. Sci., 15, 167(1994); Soc. Neurosci. Abstr., 20, 526(1994); J. Computer-Aided Mol. Design, 10, 545(1996)). Therefore, physiological activities mediated by the xcex11B receptor have not yet been completely elucidated. However, recent experiments using xcex11B transgenic mice have suggested that the xcex11B receptor is involved in vascular muscle contraction, hypercardia, and tumorigenesis (Proc. Natl. Acad. Sci. USA, 87, 2896(1990); Proc. Natl. Acad. Sci. USA, 91, 10109(1994)). Additionally, experiments using xcex11B receptor knock out mice have suggested that the xcex11B receptor is involved in vasopressor responses (Proc. Natl. Acad. Sci. USA 94, 11589(1997)). Furthermore, a variety of experiments have reported that a stimulus to the xcex11B receptor enhances the growth of vascular smooth muscle cells (J. Biol. Chem., 270, 30980(1995), and that there is a high possibility that the xcex11B receptor is involved in contraction in human coronary artery and human cerebral artery induced by a stimulus to the xcex11 receptors (xe2x80x9cKekkan to Naihixe2x80x9d (Blood Vessel and Endothelium), 6, 431(1996)), for example. Such xcex11B receptor antagonists are expected as therapeutic agents for, for example, hypertension, high ocular tension, congestive heart failure, and arrhythmia (WO97/11698) . Consequently, demands are made to create compounds having affinity for the xcex11B receptor and have high selectivity for the receptor, in order to create novel pharmaceutical agents.
The present invention therefore relates to xcex11 adrenoceptor antagonists, and it is an object of the invention to provide antagonists which are selective for the xcex11 receptor subtypes, and more specifically, to provide antagonists which have selectivity for the xcex11B adrenoceptor.
The present invention relates to an xcex11B adrenoceptor antagonist which includes a compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof: 
[wherein Ar is indole, naphthalene, quinoline, benzimidazole, benzofuran, benzothiophene, benzisoxazole, or 2-ketobenzimidazoline, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 1 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
R1 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, alkenyl having 2 to 9 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms;
B is a bond, or alkylene group having 1 to 3 carbon atoms which is unsubstituted or substituted with the groups selected from the group consisting of alkyl group having 1 to 8 carbon atoms, halogen, and hydroxy;
or Bxe2x80x94Nxe2x80x94R1 forms a ring structure and is piperidine, piperazine, or 2,3,6-trihydropyridine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms;
n denotes an integer of 0 or 1;
A is alkylene having 2 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Q is:
1) xe2x80x94NR2R3,
wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or xe2x80x94NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, 2-piperidone, 2-pyrrolidone, indoline, 2,3,4-trihydroquinoline, 2,3,4-trihydroquinoxaline, dihydrobenzoxazine, benzothiane, phthalimide, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms; or 
xe2x80x83(wherein each of R4, R5, R6 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthip group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or R4 and R5 together form an imidazoline ring)].
In another. aspect, the present invention relates to a compound represented by the general formula (III) or a pharmacologically acceptable acid addition salt thereof:
Ar2xe2x80x94Dxe2x80x94Axe2x80x94Q2xe2x80x83xe2x80x83(III)
[wherein D represents one of the following formulae 1) to 5), each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms; 
Ar2 is indole, naphthalene, quinoline, benzimidazole, benzofuran, or benzothiophene, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
A is alkylene having 3 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Q2 is:
1) xe2x80x94NR2R3,
wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkbxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms, where R2=R3=H and R2=R3=ethyl are excluded), or xe2x80x94NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, 2-piperidone, 2-pyrrolidone, indoline, 2,3,4-trihydroquinoline, 2,3,4-trihydroquinoxaline, dihydrobenzoxazine, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 oto 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arytthio group having 6 to 15 carbon atoms; or 
xe2x80x83(wherein each of R4, R5, R6 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or R4 and R5 together form an imidazoline ring)].
Of xcex11B adrenoceptor antagonists according to the present invention including a compound represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof, preferred compounds are compounds in which n is 0;
Ar is indole, naphthalene, quinoline, benzimidazole, benzofuran, or benzothiophene, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
B is alkylene having 2 or 3 carbon atoms, which is unsubstituted or substituted with the groups selected from the group consisting of alkyl group having 1 to 8 carbon atoms, halogen, and hydroxy, or
Bxe2x80x94Nxe2x80x94R1 forms a ring structure and is piperidine, piperazine, or 2,3,6-trihydropyridine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms;
Q is:
1) xe2x80x94NR2R3 (wherein each of R2 and R3 is independently hydrogen, alkylhaving 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or xe2x80x94NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, indoline, 2,3,4-trihydroquinoline, 2,3,4-trihydroquinoxaline, dihydrobenzoxazine, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and aryl thio group having 6 to 15 carbon atoms; or 
(wherein R4, R5, and R6 have the same meanings as defined above).
Among them, more preferred compounds are compounds in which n is 0;
Ar is indole, naphthalene, quinoline, or benzimidazole, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 1S carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Bxe2x80x94Nxe2x80x94R1 forms a ring structure and is piperidine or piperazine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms;
A is alkylene having 2 to 8 carbon atoms or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Q is:
1) xe2x80x94NR2R3 (wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or xe2x80x94NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms; or 
(wherein R4, R5, and R6 have the same meanings as defined above)
Of these compounds, especially preferred compounds are compounds in which n is 0;
Ar is indole or naphthalene, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Bxe2x80x94Nxe2x80x94R1 forms a ring structure and is represented by the following formula 1) or 2), each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms; 
xe2x80x83A is alkylene having 3 to 8 carbon atoms, which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Q is:
1) xe2x80x94NR2R3 (wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or xe2x80x94NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon. atoms, alkylthio group having 1 to 8 carbon atoms, and arlthio group having 6 to 15 carbon atoms; or 
(wherein R4, R5, and R6 have the same meanings as defined above).
As examples of substituents on Ar in the compounds represented by the general formula (I), halogen includes fluoro, chloro, bromo, and iodo; acylamino group having 1 to 9 carbon atoms includes xe2x80x94NHCOCH3 and xe2x80x94NHCOPh; alkylamino group having 1 to 8 carbon atoms includes methylamino, ethylamino, n-propylamino, isopropylamino, and cyclohexylamino; arylamino group having 6 to 15 carbon atoms includes phenylamino; dialkylamino group having 2 to 16 carbon atoms includes dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, and di(cyclohexyl)amino; diarylamino group having 12 to 20 carbon atoms includes diphenylamino; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; alkoxy group having 1 to 8 carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, and cyclohexyloxy; aryloxy group having 6 to 15 carbon atoms includes phenoxy; haloalkyl group having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy group having 1 to 8 carbon atoms includes trifluoromethoxy and 2,2,2-trifluoroethoxy; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 1 to 9 carbon atoms includes xe2x80x94COOMe, and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; alkylthio group having 1 to 8 carbon atoms includes methylthio, ethylthio, n-propylthio, and isopropylthio; arylthio group having 6 to 15 carbon atoms includes phenylthio; and other substituents include nitro, amino, hydroxy, cyano, and xe2x80x94COOH. Of these substituents, preferred are identical or different one or two fluoro, chloro, bromo, nitro, xe2x80x94NHCOCH3, xe2x80x94NHCOPh, amino, methylamino, ethylamino, n-propylamino, isopropylamino, phenylamino, dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, phenoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, methylthio, ethylthio, and phenylthio. Among them, more preferred are identical or different one or two fluoro, chloro, bromo, nitro, xe2x80x94NHCOCH3, amino, methylamino, isopropylamino, phenylamino, dimethylamino, diisopropylamino, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94CONH2, xe2x80x94CONMe2, methylthio, and phenylthio, of which identical or different one or two fluoro, chloro, bromo, nitro, amino, methylamino, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, and xe2x80x94CONH2 are especially preferred.
In B, preferred alkylene having 1 to 3 carbon atoms, which may be substituted with alkyl group having 1 to 8 carbon atoms, halogen, or hydroxyl group, are ethylene, 1-methylethylene, 2-methylethylene, 1-chloroethylene, 1-fluoroethylene, 2-chloroethylene, 2-fluoroethylene, 1-hydroxyethylene, 1,3-trimethylene, 1,3-(2-methyl)trimethylene, 1,3-(3-methyl)trimethylene, 1,3-(2-chloro)trimethylene, 1,3-(2-fluoro)trimethylene, 1,3-(2,2-difluoro)trimethylene, 1,3-(2-hydroxy)trimethylene, and 1,3-(1-hydroxy)trimethylene. Among them, ethylene, 2-methylethylene, 2-fluoroethylene, 1-hydroxyethylene, 1,3-trimethylene, 1,3-(2-methyl)trimethylene, 1,3-(3-methyl)trimethylene, and 1,3-(1-hydroxy)trimethylene are more preferred, of which ethylene, 1-hydroxyethylene, and 2-methylethylene are especially preferred.
When Bxe2x80x94Nxe2x80x94R1 is piperidine, piperazine, or 2,3,6-trihydropyridine, Ar is preferably substituted at the 3- or 4-position, and is typically preferably substituted at the 4-position.
As examples of substituents on piperidine, piperazine, or 2,3,6-trihydropyridine in the above case, halogen includes fluoro, chloro, and bromo; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; haloalkyl group having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COOMe, and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; hydroxyalkyl group having 1 to 8 carbon atoms includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 3-hydroxypropyl; alkylcarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COMe, and xe2x80x94COEt; arylcarbonyl having 7 to 16 carbon atoms includes xe2x80x94COPh, naphthylcarbonyl, and 2-furanylcarbonyl; aralkyl having 7 to 15 carbon atoms includes benzyl, 2-phenylethyl, and 3-phenylpropyl; and other substituents include hydroxy and xe2x80x94COOH. Among these substituents, preferred are identical or different one or two fluoro, xe2x80x94NHCOCH3, xe2x80x94NHCOPh, hydroxy, methyl, isopropyl, t-butyl, phenyl, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94SO2NPh2, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2. Among them, identical or different one or two fluoro, hydroxy, methyl, isopropyl, phenyl, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NHPh, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONHtBu, and xe2x80x94CONMe2 are more preferred, of which one fluoro, hydroxy, methyl, phenyl, trifluoromethyl, xe2x80x94SO2NH2, xe2x80x94CONH2, and xe2x80x94CONHtBu are especially preferred.
In R1, alkyl having 1 to 6 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl; aryl having 6 to 12 carbon atoms includes phenyl, naphthyl, and biphenyl; alkenyl having 2 to 9 carbon atoms includes ethenyl, 2-propenyl, 2-pentenyl, 2-octenyl, 3-butenyl, 3-hexenyl, 4-pentenyl, 4-octenyl, 1,3-butadienyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,3,5-hexatrienyl, 1,3,5-heptatrienyl, 2,4,6-heptatrienyl (these also include isomers (E form and Z form) with respect to double bond); cycloalkyl having 3 to 8 carbon atoms includes cyclopropyl, cyclobutyl, cyclohexyl, and cycloheptyl; aralkyl having 7 to 15 carbon atoms includes benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 4-phenylbutyl. Of these groups, methyl, ethyl, n-propyl, isopropyl, phenyl, 2-propenyl, cyclopropyl, cyclohexyl, benzyl, and 2-phenylethyl are preferred. Among them, methyl, phenyl, 2-propenyl, benzyl, and 2-phenylethyl are more preferred, of which methyl, phenyl, and 2-phenylethyl are especially preferred.
In A, alkylene having 2 to 8 carbon atoms includes ethylene, 1,3-trimethylene, 1,4-butylene, 1,5-pentamethylene, 1,6-hexamethylene, and 1,7-heptamethylene; phenylene includes 1,4-phenylene, and 1,3-phenylene; cycloalkylene having 3 to 8 carbon atoms includes 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, and 1,5-cyclooctylene. Among these groups, 1,3-trimethylene, 1,4-butylene, 1,5-pentamethylene, 1,6-hexamethylene, 1,4-phenylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, and 1,5-cyclooctylene are preferred, of which 1,3-trimethylene, 1,4-butylene, 1,5-pentamethylene, and 1,4-cyclohexylene are especially preferred.
As examples of substituents on the alkylene having 2 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms in A, halogen includes fluoro, chloro, bromo, and iodo; acylamino group having 1 to 9 carbon atoms includes xe2x80x94NHCOCH3 and xe2x80x94NHCOPh; alkylamino group having 1 to 8 carbon atoms includes methylamino, ethylamino, n-propylamino, isopropylamino, and cyclohexylamino; arylamino group having 6 to 15 carbon atoms includes phenylamino; dialkylamino group having 2 to 16 carbon atoms includes dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(cyclohexyl)amino, piperidino, and pyrrolidino; diarylamino group having 12 to 20 carbon atoms includes diphenylamino; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; alkoxy group having 1 to 8 carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, and cyclohexyloxy; aryloxy group having 6 to 15 carbon atoms includes phenoxy; haloalkyl group having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy group having 1 to 8 carbon atoms includes trifluoromethoxy and 2,2,2-trifluoroethoxy; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COOMe, and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; alkylthio group having 1 to 8 carbon atoms includes methylthio, ethylthio, n-propylthio, and isopropylthio; arylthio group having 6 to 15 carbon atoms includes phenylthio; and other substituents include nitro, amino, hydroxy, cyano, and xe2x80x94COOH. Among these substituents, identical or different one or more fluoro, chloro, amino, methylamino, isopropylamino, phenylamino, dimethylamino, 1-piperidino, 1-pyrrolidino, hydroxy, methyl, isopropyl, phenyl, methoxy, isopropoxy, phenoxy, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94SO2NPh2, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2 are preferred, of which identical or different one or more fluoro, amino, methylamino, 1-piperidino, hydroxy, methyl, isopropyl, methoxy, and trifluoromethyl are especially preferred.
Of R2, R3, R4, R5, and R6 in Q, alkyl having 1 to 6 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl; cycloalkyl having 3 to 8 carbon atoms includes cyclopropyl, cyclobutyl, cyclohexyl, and cycloheptyl; aryl having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; aralkyl having 7 to 15 carbon atoms includes benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 4-phenylbutyl; alkenyl having 2 to 9 carbon atoms includes ethenyl, 2-propenyl, 2-pentenyl, 2-octenyl, 3-butenyl, 3-hexenyl, 4-pentenyl, 4-octenyl, 1,3-butadienyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,3,5-hexatrienyl, 1,3,5-heptatrienyl, and 2,4,6-heptatrienyl (these also include isomers (E form and Z form) with respect to double bond). Of these groups, methyl, n-propyl, cyclopropyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, and 2-propenyl are preferred. Among them, methyl, cyclopropyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, and 2-propenyl are more preferred, of which methyl, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-propenyl are especially preferred.
When R2, R3, R4, R5, and R6 are aryl having 6 to 15 carbon atoms or aralkyl having 7 to 15 carbon atoms, as examples of substituents on the aryl, halogen includes fluoro, chloro, and bromo; acylamino group having 1 to 9 carbon atoms includes xe2x80x94NHCOCH3 and xe2x80x94NHCOPh; alkylamino group having 1 to 8 carbon atoms includes methylamino, ethylamino, n-propylamino, isopropylamino, and cyclohexylamino; arylamino group having 6 to 15 carbon atoms includes phenylamino; dialkylamino group having 2 to 16 carbon atoms includes dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(cyclohexyl)amino, piperidino, and pyrrolidino; diarylamino group having 12 to 20 carbon atoms includes diphenylamino; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; alkoxy group having 1 to 8 carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, and cyclohexyloxy; aryloxy group having 6 to 15 carbon atoms includes phenoxy; haloalkyl group having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy group having 1 to 8 carbon atoms includes trifluoromethoxy and 2,2,2-trifluoroethoxy; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COOMe, and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; alkylthio group having 1 to 8 carbon atoms includes methylthio, ethylthio, n-propylthio, and isopropylthio; arylthio group having 6 to 15 carbon atoms includes phenylthio; and other substituents include nitro, amino, hydroxy, cyano, and xe2x80x94COOH. Among these substituents, identical or different one or more fluoro, chloro, amino, methylamino, isopropylamino, phenylamino, dimethylamino, 1-piperidino, 1-pyrrolidino, hydroxy, methyl, isopropyl, phenyl, methoxy, isopropoxy, phenoxy, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94SO2NPh2, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2 are preferred, of which identical or different one or more fluoro, amino, methylamino, 1-piperidino, hydroxy, methyl, phenyl, isopropyl, methoxy, trifluoromethyl, xe2x80x94SO2NH2, and xe2x80x94CONH2 are especially preferred.
As Q, preferred are methylamine, 2-phenylethylamine, piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, dimethylamine, di(2-phenylethyl)amine, isoindoline, piperazine, morpholine, 2-piperidone, 1-guanidine, and 2-imidazoline. Among them, 2-phenylethylamine, piperidine, 1,3,4-trihydroisoquinoline, dimethylamine, di(2-phenylethyl)amine, isoindoline, and 2-imidazoline are more preferred, of which 2-phenylethylamine, piperidine, 1,3,4-trihydroisoquinoline, isoindoline, and 2-imidazoline are especially preferred.
Of compounds represented by the general formula (III) or pharmacologically acceptable acid addition salts thereof according to the present invention, preferred compounds are compounds in which D represents one of the following formulae 1) to 3), each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group, having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms; 
Ar2 is indole, naphthalene, quinoline, or benzimidazole, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
A is an alkylene having 3 to 8 carbon atoms or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Q2 is:
1) xe2x80x94NR2R3,
wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms, where R2=R3=H and R2=R3=ethyl are excluded), or xe2x80x94NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, indoline, 2,3,4-trihydroquinoline, 2,3,4-trihydroquinoxaline, dihydrobenzoxazine, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms and arylthio group having 6 to 15 carbon atoms; or 
(wherein each of R4, R5, R6 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or R4 and R5 together form an imidazoline ring).
In more preferred compounds, D represents one of the following formulae 1) and 2), each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms; 
Ar2 is indole or naphthalene, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
A is alkylene having 3 to 8 carbon atoms, which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
Q2 is:
1) xe2x80x94NR2R3,
wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms, where R2=R3=H and R2=R3=ethyl are excluded), or xe2x80x94NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms,iaryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms; or 
(wherein R4, R5, and R6 have the same meanings as defined above).
As examples of substituents on Ar2 in the compounds (III), halogen includes fluoro, chloro, bromo, and iodo; acylamino group having 1 to 9 carbon atoms includes xe2x80x94NHCOCH3 and xe2x80x94NHCOPh; alkylamino group having 1 to 8 carbon atoms includes methylamino, ethylamino, n-propylamino, isopropylamino, and cyclohexylamino; arylamino group having 6 to 15 carbon atoms includes phenylamino; dialkylamino group having 2 to 16 carbon atoms includes dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, and di(cyclohexyl)amino; diarylamino group having 12 to 20 carbon atoms includes diphenylamino; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atomsiincludes phenyl, naphthyl, and biphenyl; alkoxy group having 1 to 8 carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, and cyclohexyloxy; aryloxy group having 6 to 15 carbon atoms includes phenoxy; haloalkyl group.having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl;.haloalkoxy group having 1 to 8 carbon atoms includes trifluoromethoxy and 2,2,2-trifluoroethoxy; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 1 to 9 carbon atoms includes xe2x80x94COOMe, and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; alkylthio group having 1 to 8 carbon atoms includes methylthio, ethylthio, n-propylthio, and isopropylthio; arylthio group having 6 to 15 carbon atoms includes phenylthio; and other substituents include nitro, amino, hydroxy, cyano, and xe2x80x94COOH. Of these substituents, identical or different one or two fluoro, chloro, bromo, nitro, xe2x80x94NHCOCH3, xe2x80x94NHCOPh, amino, methylamino, ethylamino, n-propylamino, isopropylamino, phenylamino, dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, phenoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, methylthio, ethylthio, and phenylthio are preferred. Among them, identical or different one or two fluoro, chloro, bromo, nitro, xe2x80x94NHCOCH3, amino, methylamino, isopropylamino, phenylamino, dimethylamino, diisopropylamino, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94CONH2, xe2x80x94CONMe2, methylthio, and phenylthio are more preferred, of which identical or different one or two fluoro, chloro, bromo, nitro, amino, methylamino, 2-phenylethylamino, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, and xe2x80x94CONH2 are especially preferred.
As examples of substituents on D, halogen includes fluoro, chloro, and bromo; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; haloalkyl group having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COOMe and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms. includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; hydroxyalkyl group having 1 to 8 carbon atoms includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 3-hydroxypropyl; alkylcarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COMe, and xe2x80x94COEt; arylcarbonyl having 7 to 16 carbon atoms includes xe2x80x94COPh, naphthylcarbonyl, and 2-furanylcarbonyl; aralkyl having 7 to 15 carbon atoms includes benzyl, 2-phenylethyl, and 3-phenylpropyl; and other substituents include hydroxy and xe2x80x94COOH. Among these substituents, identical or different one or two fluoro, xe2x80x94NHCOCH3, xe2x80x94NHCOPh, hydroxy, methyl, isopropyl, t-butyl, phenyl, trifluoromethyl, trifluoromethoxy, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94SO2NPh2, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2 are preferred. Among them, identical or different one or two fluoro, hydroxy, methyl, isopropyl, phenyl, trifluoromethyl, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NHPh, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONHtBu, and xe2x80x94CONMe2 are more preferred, of which one fluoro, hydroxy, methyl, phenyl, trifluoromethyl, xe2x80x94SO2NH2, xe2x80x94CONH2, and xe2x80x94CONHtBu are especially preferred.
In A, alkylene having 3 to 8 carbon atoms includes 1,3-trimethylene, 1,4-butylene, 1,5-pentamethylene, 1,6-hexamethylene, and 1,7-heptamethylene; phenylene includes 1,4-phenylene and 1,3-phenylene; cycloalkylene having 3 to 8 carbon atoms includes 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, and 1,5-cyclooctylene. Among these groups, 1,3-trimethylene, 1,4-butylene, 1,5-pentamethylene, 1,6-hexamethylene, 1,4-phenylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, and 1,5-cyclooctylene are preferred, of which 1,3-trimethylene, 1,4-butylene, 1,5-pentamethylene, and 1,4-cyclohexylene are especially preferred.
As examples of substituents on the alkylene having 3 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms in A, halogen includes fluoro, chloro, bromo, and iodo; acylamino group having 1 to 9 carbon atoms includes xe2x80x94NHCOCH3 and xe2x80x94NHCOPh; alkylamino group having 1 to 8 carbon atoms includes methylamino, ethylamino, n-propylamino, isopropylamino, and cyclohexylamino; arylamino group having 6 to 15 carbon atoms includes phenylamino; dialkylamino group having 2 to 16 carbon atoms includes dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(cyclohexyl)amino, piperidino, and pyrrolidino; diarylamino group having 12 to 20 carbon atoms includes diphenylamino; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; alkoxy group having 1 to 8 carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, and cyclohexyloxy; aryloxy group having 6 to 15 carbon atoms includes phenoxy; haloalkyl group having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy group having 1 to 8 carbon atoms includes trifluoromethoxy and 2,2,2-trifluoroethoxy; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COOMe and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; alkylthio group having 1 to 8 carbon atoms includes methylthio, ethylthio, n-propylthio, and isopropylthio; arylthio group having 6 to 15 carbon atoms includes phenylthio; and other substituents include nitro, amino, hydroxy, cyano, and xe2x80x94COOH. Among these substituents, identical or different one or more fluoro, chloro, amino, methylamino, is6propylamino, phenylamino, dimethylamino, 1-piperidino, 1-pyrrolidino, hydroxy, methyl, isopropyl, phenyl, methoxy, isopropoxy, phenoxy, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94SO2NPh2, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2 are preferred, of which identical or different one or more fluoro, amino, methylamino, 1-piperidino, hydroxy, methyl, isopropyl, methoxy, and trifluoromethyl are especially preferred.
Of R2, R3, R4, R5, and R6 in Q2, alkyl having 1 to 6 carbon atoms includes methyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl; cycloalkyl having 3 to 8 carbon atoms includes cyclopropyl, cyclobutyl, cyclohexyl, and cycloheptyl; aryl having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; aralkyl having 7 to 15 carbon atoms includes benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 4-phenylbutyl; alkenyl having 2 to 9 carbon atoms includes ethenyl, 2-propenyl, 2-pentenyl, 2-octenyl, 3-butenyl, 3-hexenyl, 4-pentenyl, 4-octenyl, 1, 3-butadienyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,3,5-hexatrienyl, 1,3,5-heptatrienyl, and 2,4,6-heptatrienyl (these also include isomers (E form and Z form) with respect to double bond). Of these groups, methyl, n-propyl, cyclopropyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, and 2-propenyl are preferred. Among them, methyl, cyclopropyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 4phenylbutyl, and 2-propenyl are more preferred, of which methyl, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-propenyl are especially preferred.
When R2, R3, R4, R5, and R6 are aryl having 6 to 15 carbon atoms or,aralkyl having 7 to 15 carbon atoms, as examples of substituents on the aryl, halogen includes, fluoro, chloro, and bromo; acylamino group having 1 to 9 carbon atoms includes xe2x80x94NHCOCH3 and xe2x80x94NHCOPh; alkylamino group having 1 to 8 carbon atoms includes methylamino, ethylamino, n-propylamino, isopropylamino, and cyclohexylamino; arylamino grouphaving 6 to 15 carbon atoms includes phenylamino; dialkylamino group having 2 to 16 carbon atoms includes dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(cyclohexyl)amino, piperidino, and pyrrolidino; diarylamino group having 12 to 20 carbon atoms includes diphenylamino; alkyl group having 1 to 8 carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl; aryl group having 6 to 15 carbon atoms includes phenyl, naphthyl, and biphenyl; alkoxy group having 1 to 8 carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, and cyclohexyloxy; aryloxy group having 6 to 15 carbon atoms includes phenoxy; haloalkyl group having 1 to 8 carbon atoms includes trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy group having 1 to 8 carbon atoms includes trifluoromethoxy and 2,2,2-trifluoroethoxy; aminosulfonyl group having 0 to 15 carbon atoms includes xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, and xe2x80x94SO2NPh2; alkoxycarbonyl group having 2 to 9 carbon atoms includes xe2x80x94COOMe and xe2x80x94COOEt; aminocarbonyl group having 1 to 15 carbon atoms includes xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2; alkylthio group having 1 to 8 carbon atoms includes methylthio, ethylthio, n-propylthio, and isopropylthio; arylthio group having 6 to 15 carbon atoms includes phenylthio; and other substituents include nitro, amino, hydroxy, cyano, and xe2x80x94COOH. Among these substituents, identical or different one or more fluoro, chloro, amino, methylamino, isopropylamino, phenylamino, dimethylamino, 1-piperidino, 1-pyrrolidino, hydroxy, methyl, isopropyl, phenyl, methoxy, isopropoxy, phenoxy, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94SO2NH2, xe2x80x94SO2NHMe, xe2x80x94SO2NMe2, xe2x80x94SO2NHPh, xe2x80x94SO2NPh2, xe2x80x94COOH, xe2x80x94COOMe, xe2x80x94CONH2, xe2x80x94CONHMe, xe2x80x94CONMe2, xe2x80x94CONHtBu, xe2x80x94CONHPh, and xe2x80x94CONPh2 are preferred, of which identical or different one or more fluoro, amino, methylamino, 1-piperidino, hydroxy, methyl, phenyl, isopropyl, methoxy, trifluoromethyl, xe2x80x94SO2NH2, and xe2x80x94CONH2 are especially preferred.
As Q2, methylamine, 2-phenylethylamine, piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, dimethylamine, di(2-phenylethyl)amine, isoindoline, piperazine, morpholine, 2-piperidone, 1-guanidine, and 2-imidazoline are preferred. Among them, 2-phenylethylamine, piperidine, 1,3,4-trihydroisoquinoline, dimethylamine, di(2-phenylethyl)amine, isoindoline, and 2-imidazoline are more preferred, of which 2-phenylethylamine, piperidine, 1,3,4-trihydroisoquinoline, isoindoline, and 2-imidazoline are especially preferred.
Pharmacologically preferable acid addition salts include, but are not limited to, hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates, and other inorganic acid salts; acetates, lactates, citrates, oxalates, glutarates, malates, tartrates, fumarates, mandelates, maleates, benzoates, phthalates, and other organic carboxylates; methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, and other organic sulfonates. Among them, hydrochlorides, phosphates, tartrates, and methanesulfonates are especially preferred.
Specific examples of the compounds represented by the general formula (I) or general formula (III) according to the invention are shown in the following tables, which are not intended to limit the scope of the present invention.
Of the invented compounds, there are a variety of optical isomers when the compound in question has an asymmetric carbon in the molecule, and there are a variety of diastereomers when the compound has at least two asymmetric carbons. The present invention also includes these optical isomers and individual isomers. Additionally, the present invention also includes stereoisomers.
Some compounds of the compounds of the general formula (I) according to the invention have already been disclosed in literature [Arch. Pharm. Pharm. Med. Chem., 329, 3(1996)] or PCT International Publication No. WO94/24127, and the production process described therein can be applied as intact.
Generally, the compounds are produced by, for example, (1) an N-alkylation using amine (IV) and alkyl halide (V) in the presence of an appropriate base (scheme 1-1), (2) an N-alkylation using haloalkylamide (VI) and amine (VII) in the presence of an appropriate base (scheme 1-2), or (3) a reductive amination using an appropriate aldehyde Arxe2x80x94Bxe2x80x2xe2x80x94CHO (wherein Bxe2x80x2 is bond, or alkylene having 1 to 3 carbon atoms, which is unsubstituted or substituted with alkyl group having 1 to 8 carbon atoms, halogen, or hydroxy), and a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride and the like or a hydrogenation (scheme 1-3), as shown in scheme 1: 
(wherein Ar, B, R1, A, and Q have the same meanings as defined above; and each of X1 and x2 is chloro, bromo, iodo, methanesulfonyloxy, or p-toluenesulfonyloxy).
The N-alkylation performed in scheme 1-1 according to the present invention can be performed by conventionally known techniques. The solvents include an alcoholic solvent such as methanol, ethanol and the like; an etherial solvent such as dioxane, THF and the like; an aprotic solvent such as DMF, DMSO, acetonitrile and the like. Among them, acetonitrile and DMF are preferably employed, and the use of acetonitrile generally yields satisfactory results. The bases include a metal hydroxide such assodium hydroxide, potassium hydroxide and the like; a metal alkoxide such as sodium alkoxides, potassium alkoxides andthe like; a metal hydride such as sodium hydride, potassium hydride and the like; an alkylmetal such as n-butyllithium, methyllithium and the like; a metal carbonate such as sodium hydrogencarbonate, potassium carbonate, sodium carbonate and the like; a tertiary amine such as trialkylamines, diisopropylethylamine and the like. Among them, sodium hydride, potassium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine are preferably employed, and the use of potassium carbonate generally yields satisfactory results. The equivalent of the base used is not specifically limited, but the use of 1 to 50 equivalents, preferably 2 to 20 equivalents, and more preferably 2 to 10 equivalents relative to amine (IV) generally yields satisfactory results. The equivalent of alkyl halide or the like (V) used is not specifically limited, but the use of 0.5 to 10 equivalents, preferably 0.8 to 5 equivalents, and more preferably 1 to 3 equivalents relative to amine (IV) generally yields""satisfactory results. The reaction is generally performed at a reaction temperature in a range of 20xc2x0 C. to 150xc2x0 C., preferably in a range of 40xc2x0 C. to 120xc2x0 C., and more preferably in a range of 60xc2x0 C. to 100xc2x0 C. The reaction time generally falls in a range of 30 minutes to 150 hours, preferably in a range of 1 hour to 72 hours, and more preferably in a range of 2 hours to 24 hours.
The N-alkylation performed in scheme 1-2 according to the present invention can be carried out in the same manner as in scheme 1-1. The solvents include an alcoholic solvent such as methanol, ethanol and the like; an etherial solvent such as dioxane, THF and the like; an aprotic solvent such as DMF, DMSO, acetonitrile and the like. Among them, acetonitrile and DMF are preferably employed, and the use of acetonitrile generally yields satisfactory results. The bases include a metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; a metal alkoxide such as sodium alkoxides, potassium alkoxides and the like; a metal hydride such as sodium hydride, potassium hydride and the like; an alkylmetal such as n-butyllithium, methyllithium and the like; a metal carbonate such as sodium hydrogencarbonate, potassium carbonate, sodium carbonate and the like; a tertialy amine such as trialkylamines and the like. Among them, sodium hydride, potassium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine are preferably employed, and the use of potassium carbonate generally yieldssatisfactory results. The equivalent of the base used is not specifically limited, but the use of 1 to 50 equivalents, preferably 2 to 20 equivalents, and more preferably 2 to 10 equivalents relative to haloalkylamide (VI) generally yields satisfactory results. When 3 equivalents or more of amine (VII) is used, satisfactory results can be obtained without the addition of a base. The equivalent of amine (VII) used is not specifically limited, but the use of 1 to 50 equivalents, preferably 1 to 30 equivalents, and more preferably 2 to 5 equivalents relative to haloalkylamide (VI) generally yields satisfactory results. The reaction is generally performed at a reaction temperature in a range of 20xc2x0 C. to 150xc2x0 C., preferably in a range of 40xc2x0 C. to 120xc2x0 C., and more preferably in a range of 60xc2x0 C. to 100xc2x0 C. The reaction time generally falls in a range of 30 minutes to 150 hours, preferably in a range of 1 hour to 72 hours, and more preferably in a range of 2 hours to 24 hours.
The reductive amination performed in scheme 1-3 according to the invention can be performed by conventionally known techniques. The solvents include a halogen solvent such as 1,2-dichloroethane, dichloromethane and the like; an etherial solvent such as THF and the like; an alcoholic solvent such as methanol, ethanol and the like; and acetonitrile and the like. Among them, 1,2-dichloroethane and THF are preferably employed, and the use of 1,2-dichloroethane generally yields satisfactory results. The reducing agents include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, borane-pyridine complexes and the like. Among them, sodium cyanoborohydride and sodium triacetoxyborohydride are preferably employed, and the use of sodium triacetoxyborohydride generally yields satisfactory results. The equivalent of the reducing agent used is not specifically limited, but the use of 0.5 to 20 equivalents, preferably 1 to 10 equivalents, and more preferably 1.5 to 3 equivalents relative to aldehyde (VIII) generally yields satisfactory results. The equivalent of amine (IX) used is not specifically limited, but the use of 0.5 to 10 equivalents, preferably 0.8 to 5 equivalents, and more preferably 1 to 3 equivalents relative to aldehyde (VIII) generally yields satisfactory results. The reaction is generally performed at a reaction temperature in a range of xe2x88x9278xc2x0 C. to 150xc2x0 C., preferably in a range of xe2x88x9220xc2x0 C. to 100xc2x0 C., and more preferably in a range of 0xc2x0 C. to 40xc2x0 C. The reaction time generally falls in a range of 30 minutes to 150 hours, preferably in a range of 1 hour to 72 hours, and more preferably in a range of 2 hours to 24 hours.
Commercially available compounds as intact can be used as these compounds (IV) to (IX) for use in the reactions. Additionally, compounds which are not commercially available can be prepared by the application of techniques known to those skilled in the art and described in the following references and patents.
Amine derivative (IV) can be prepared by the application of techniques known to those skilled in the art and disclosed in J. Heterocycl. Chem., 19, 377(1982); WO 9218505; Japanese Unexamined Patent Application Publication No. 1-207288; Angew. Chem. Int. Ed. Engl., 34, 1348(1995); J. Org. Chem., 62, 1268(1997); EP 714894 and the like.
Haloalkylamine derivative (V) can be prepared by the application of techniques known to those skilled in the art and disclosed in WO9218505; J. Chem. Soc., Chem. Commun., 960(1983); J. Am. Chem. Soc., 87, 67(1945); Acta. Chim. Hung., 128, 375(1991); Pharmazie, 21(1996) and the like.
Amide derivative (VI) can be prepared from amine derivative (IV) by the application of amidation disclosed in J. Med. Chem., 34, 593(1991); Farmaco. Ed. Sci., 45(933); and J. Heterocycl. Chem., 33, 427(1996).
Diamine derivative (IX) can be prepared by the application of techniques known to those skilled in the art and disclosed in. J. Med. Chem., 34, 942(1991); Czech. Chem. Commu., 56, 1725(1991); J. Org. Chem., 61, 3635(1996) and the like.
As shown in the following examples, the compounds represented by the general formula (I) or general formula (III) according to the present invention are antagonists having high affinity and selectivity for the xcex11B adrenoceptor, and can be used for therapy of diseases in which the xcex11B adrenoceptor is concerned, and are particularly useful as therapeutic agents for circulatory diseases.
The xe2x80x9ctherapeutic agents for circulatory diseasesxe2x80x9d used herein include inhibitory agents of vascular intimal thickening, therapeutic agents for ischemic diseases, therapeutic agents for cardiac diseases, and therapeutic agents for hypertension. The inhibitory agents of vascular intimal thickening are pharmaceutical agents for use in therapy or prophylaxis of angiostenosis due to hypertrophy of vascular smooth muscle cells, more specifically, of arteriosclerosis and restenosis after percutaneous transluminal coronary angioplasty (PTCA). The therapeutic agents for ischemic diseases are pharmaceutical agents for use in therapy or prophylaxis of cardiac or cerebral disorders caused by ischaemia due to, for example, hypervasoconstriction, specifically of angina pectoris, or cerebrovascular spasm after subarachnoid hemorrhage. The therapeutic agents for cardiac diseases are pharmaceutical agents for use in therapy or prophylaxis of, for example, arrhythmia, cardiac hypertrophy, and heart failure. The therapeutic agents for hypertension are pharmaceutical agents for use in therapy or prophylaxis of increased blood pressure due to increased resistance of peripheral vessels, specially of essential hypertension, renovascular hypertension, renal parenchymal hypertension, endocrine hypertension, vascular hypertension, hypertension in patients with dialysis and patients with renal transplantation, and hypertension due to pheochromocytoma. The compounds according to the present invention are especially useful as therapeutic agents for hypertension.
Additionally, the compounds according to the invention exhibit antagonism against the xcex11B receptor and can also be used as, for example, antineoplastic agents, ocular tension depressants, and therapeutic agents for prostatism. The antineoplastic agents as used herein mean pharmaceutical agents for use in therapy of carcinoma or sarcoma; the ocular tension depressants mean pharmaceutical agents for use in therapy or prophylaxis of various diseases in which the ocular tension increases, specifically of primary open angle glaucoma, primary angle-closure glaucoma, secondary glaucoma, congenital glaucoma, and ocular hypertension. The therapeutic agents for prostatism mean pharmaceutical agents for use in therapy or prophylaxis of tumescent prostate gland or irritation symptom or occlusion symptom due to such tumentia.
Additionally, the compounds according to the present invention are useful to clarify physiological activities mediated by the xcex11B adrenoceptor, and can be used as pharmacological tools to verify whether the xcex11B receptor is concerned in various diseases or not.
When the invented xcex11B adrenoceptor antagonist is clinically used as a pharmaceutical agent, the agent may be a free base or a salt thereof as intact or may further comprise appropriate additives. Such additives include excipients, stabilizers, preservatives, buffers, solubilizing agents, emulsifying agents, diluents, and isotonizing agents. As the form of administration, any of parenteral (non-oral) administration and oral administration yields sufficient. effects. Administration formulations include injections, tablets, liquids, capsules, granules, powders and the like, and these formulations can be produced by known formulation techniques. A dose can be appropriately selected depending on the symptom, age, weight of the patient and dosage method, and the amount of active ingredient per day per adult is 0.0001 mg to 10 g, and preferably 0.001 mg to 1 g. The agent can be administered once or in several installments per day.